Hydroxy-substituted benzophenones and analogs thereof refer to derivatives having more than one hydroxyl substitutions in the two benzene rings of benzophenone, such as 2,2′-dihydroxybenzophenone, 2,2′3′-trihydroxybenzophenone, 2,4,2′,4′-tetrahydroxybenzophenone, 2,3,4-trihydroxybenzophenone, 2,2′,3′-trihydroxybenzophenone, 2,3,4,2′,3′,4′-hexahydroxybenzophenone, 2,3,4,2′,4′,5-hexahydroxybenzophenone, 2,3,3′,4,4′,5-hexahydroxybenzophenone and the like. At present, many of these hydroxyl-substituted benzophenones and analogues thereof are used as UV absorbers and several of them are also used for cardiovascular and cerebrovascular drugs, such as exifone (chemical name as 3,4,5,2′,3′,4′-hexahydroxybenzophenone) developed by Pharmascience in France and put on the market as an intelligent improvement drug in 1988, which has functions of increasing cerebral blood flow, reducing cerebral capillary permeability and improving learning and memory capability.
Human immunodeficiency virus (HIV), human papilloma virus (HPV) and herpes virus (HSV) have characteristics of being integrated into the human cells and long-term retention, but each has different genetic and metabolic characteristics.
HIV-1 is a virus that causes AIDS, and encodes three enzymes: reverse transcriptase (RT), protease (PR) and integrase (IN). These three enzymes are basic enzymes essential for HIV replication and infection. Integrase inhibitor with novel mechanisms of action can improve efficacy and work synergistically with existing anti-AIDS drugs to form a new and effective combination therapy. HIV-1 integrase (IN) is one of the three basic enzymes essential for viral replication. Retroviral DNA is inserted into the host chromosomes under the catalysis of the integrase, so that the virus can be replicated after it is integrated with human chromosomes. The integrase controls the HIV to invade the chromosomes, so the integrase inhibitors can inhibit the HIV from invading the chromosomes of normal cells. This is now believed as a great breakthrough in the field of anti-AIDS drug development. HIV-1 integrase acts at a single active site with two DNA substrates of the virus and host having different conformations, which may limit HIV to generate drug resistance to integrase inhibitors; furthermore, the integrase only exists in viruses, and mammals have no such enzyme, so HIV-1 integrase becomes a promising new target protein for anti-HIV drug design (Curr. Opin. Drug. Discov. Devel. 2001, 4, 402-410). Many HIV-1 integrase inhibitors have been identified, some compounds of which show the activity of selectively inhibiting HIV-1 integrase and blocking viral replication, and the two most influential inhibitors are polyhydroxy aromatic ring compounds containing catechol and aryl β-diketonic acid compounds as recently reported. However, they are significantly different from the hydroxybenzophenone in structures.
Alzheimer's disease is the most common dementia disease. Many studies of Alzheimer's disease in recent years have revealed the relation between the infection of type 1 herpes simplex virus and the individuals suffering from Alzheimer's disease. Most people in their bodies carry herpes simplex virus, and during the initial infection of the bodies, the virus will be extremely active and cause the bodies to generate oral ulcers or lips herpes. Herpes virus is a neurotropic virus, and can enter into the nerve tissues and exist for long terms after infection. It is now believed that the accumulation of beta-pastein plaques is the main cause of Alzheimer's disease and that the lip-herpes virus may play an important role in the formation of such plaques. The researchers have detected DNA of the lips herpes virus in the protein plaques using the precise gene analysis technique of “In-situ Polymerization-Chain Reaction” (IS-PCR), which indicates that the virus may lead to the formation of protein plaques. When cells are cultured in the laboratory, the lips herpes virus contributes to the formation of beta-pastein plaques. The researchers, by using the precise gene analysis technique of “In-situ Polymerase Chain Reaction Amplification” (IS-PCR), have detected DNA of the lips herpes virus in the protein plaques, which indicates that the virus may lead to the formation of protein plaques. In two study reports published in the international magazine Alzheimer's & Dementia on Oct. 22, 2014, the researchers from Umea University in Sweden find that the infection of herpes simplex virus may increase the risk of suffering from the Alzheimer's disease for individuals. The study results the clearly analyze the association of herpes simplex virus infection with suffering the Alzheimer's disease; in the first study which conducts a follow-up study long up to an average of 11.3 years on 3,432 individuals, the researchers reveal that the re-activation of herpes virus can double the risk of suffering from the Alzheimer's disease for individuals; in the second study, the researchers detect the body samples of 360 patients with Alzheimer's disease as donated in Medical Biological Library of Umea University. The result shows that the risk of suffering from Alzheimer's disease will be doubled if individuals carry herpes virus. Finally, the researchers conclude that if we use antiviral drugs to treat herpes virus infection, there is a promise of inhibiting and treating Alzheimer's disease of individuals by using the antiviral drugs, and it is possible to develop a novel therapy for treating Alzheimer's disease.
Human papillomavirus (HPV) is closely related to the induction of a variety of mucocutaneous inflammations and cancers, such as genital warts, flat warts, common warts, cervicitis, cervical erosion, oral cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, lung cancer and cervical cancer. Genital warts, flat warts and common warts, which are benign mucocutaneous neoplasm caused by human papillomavirus (HPV), are one of the most common transmissible diseases. Human papillomavirus (HPV) has more than 100 subtypes, in which some high-risk subtypes such as type 16, type 18, type 33, type 52 and type 58 viruses are proved to be able to be integrated into the cervical mucosal cell DNA and unable to be killed by the existing drugs, thereby inducing cervical cancer, oral cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer and skin cancer. Studies show that high-risk human papillomavirus, as the same as smoking, is an important inducement to lung cancer.
HPV can, through the placenta and childbirth process, lead to a vertical transmission from mother to a child, so as to cause the next generation born with a virus and disable the preventive vaccines to work.
In recent years, study results show that 29.3% of patients with cervical erosion have positive HPV and the chance of normal cervix being positive is only 11.1% (Fuqiang CHEN et. al., Journal of Cancer Prevention and Treatment, 2001, 8 (4) 342-344; Chengkang X U, Academic Journal of Sun Yat-sen University of Medical Sciences, 1998, 19 (3): 223-226). According to reports (Ahn ws et al, J Cell Biochem Suppl, 1997; 28-29: 133-139), the expression rate of the high-risk HPV (human papillomavirus) type 16 and type 18 among the patients with the chronic cervicitis is 69%, the detection rate of the high-risk type HPV16 and HPV18 exhibits an increasing trend with the increase of the degree of cervical erosion, the detection rate of the granular or papillary erosion HPV16 and HPV18 are significantly different as compared with that of the normal cervix. It is detected by PCR that the positive rate of HPV16 and HPV18 in cervical cancer reaches 83.33%, and the high-risk HPV DNA is integrated into the chromosomes of host cells, so as to produce tumor proteins E6 and E7 which inhibit the anti-oncogenes p53 and Rb respectively to help cells to escape from the control of p53 and Rb, so as to cause the cell cycle out of control, and consequently the cells normally in a static state actively proliferates and tumors grow. If HPV type 16 and type 18 persist, cytopathic effects of the cervix can be progressed. Cervical HPV infection is different from vulvar infection, since in convex, HPV type 16/18 as a main role commonly causes no warts change, but exists as a recessive infection in a long term, which firstly causes atypical hyperplasia and then cancers while other factors are involved in. Currently, there is relatively a lack of effective drugs for treating genital warts and cervical erosion, because some drugs such as podophyllotoxin d have the problem of being very irritating and generating great toxic side effects, despite the advantage of short treatment course. Specific symptoms thereof are pain, edema, erosion and so on. Recombinant human interferon α-2β gel as an external drug for treating genital warts is commonly recognized an effective drug currently. But these drugs cannot eradicate the virus integrated into the human cells, so the infection lasts for a long time and is unhealed, and finally transforms into a malignant tumor.
Malignant tumors are a serious threat to human health and life. At present, chemotherapy drugs for the clinical application are relatively very toxic, and have poor effects on solid tumors, and the vast majority of patients receiving chemotherapy eventually died of tumor cell metastasis. Therefore, it is a main task for the tumor chemotherapy study to peruse a drug having low toxicity and capable of inhibiting the tumor growth and metastasis.
People have been developing anti-HIV, HSV and HPV virus infection and anti-tumor new drugs.
3,4,5-trihydroxybenzoic acid and its glucose-derived derivatives have the effect of inhibiting HIV-1 integrase (Kane C J et al., Planta Med 2002 May; 68 (5): 457-9), but its activity is not high.
CN1234353C discloses the use of 3,4,5-trihydroxybenzoic acid for antitumor, in particular anti-hepatocellular carcinoma and cervical cancer. But 3,4,5-trihydroxybenzoic acid is known to be unstable in human environmental conditions.